How Sun and Smoke Trigger Cancer

Sequencing tumor genomes reveals the origins of some cancer-causing mutations.

Smokers may develop a mutation for every 15 cigarettes smoked,
according to new analysis of the genome of a tumor from a lung cancer patient.
By comparing the patient’s normal genome sequence to the sequence of the tumor,
scientists at the Wellcome Trust Sanger Institute, in
London, found that the tumor cells had acquired more than 23,000 mutations,
according to research published in Nature
on Thursday.

Researchers at the, also sequenced
the tumor of a patient with melanoma, which contained more than 30 000
mutations, many of which can be linked to exposure to ultraviolet light. They say the findings will shed light on how environmental
factors trigger the genetic changes that ultimately lead to cancer.

“These are the two main cancers in the developed world
for which we know the primary exposure,” explains Professor Mike Stratton,
from the Cancer Genome Project at the Wellcome Trust Sanger Institute, in a statement
from the Wellcome Trust. “For lung cancer, it is cigarette smoke and for
malignant melanoma it is exposure to sunlight. With these genome sequences, we
have been able to explore deep into the past of each tumour, uncovering with
remarkable clarity the imprints of these environmental mutagens on DNA, which
occurred years before the tumour became apparent. We can also see the desperate
attempts of our genome to defend itself against the damage wreaked by the
chemicals in cigarette smoke or the damage from ultraviolet radiation. Our
cells fight back furiously to repair the damage, but frequently lose that
fight.”

When the researchers analyzed the 23,000 mutations, they found
distinctive patterns associated with the cocktail of carcinogens present in
cigarette smoke. The DNA sequence of the cancer cells also revealed that the
cells had attempted to repair their smoke-damaged DNA using two mechanisms, but
the cells were only partially successful.

“By applying the same approach to other cancers not associated with
cigarette smoking, including the very large group of people who develop lung
cancer but have never smoked, it may be possible to discern which carcinogens
play a role in those other cancers as well,” said [Dr. Adi Gazdar, a professor
of pathology in the Hamon Center at UT Southwestern, who provided the lung
cancer cells and normal cells for the research.]

“It’s like doing an archaeological excavation,” said Professor Mike Stratton,
of the Cancer Genome Project at the Sanger Institute. “We can see traces and
imprints of all these processes that have been operating for decades before the
cancer became symptomatic. This will be fundamental to understanding the causes
of cancers and how we treat and prevent them.”

The next challenge for scientists is to determine which of these thousands
of mutations are harmless “passengers”, and which are the critical drivers of
the disease. This will involve sequencing DNA from hundreds more tumours to
identify mutations that occur again and again.

When such driver mutations are found, they will immediately become
attractive targets for the development of new drugs that can shut them down,
without harming healthy tissue and causing the distressing side-effects of
present chemotherapy and radiotherapy.

To map the mutations, the scientists sequenced the genetic code of tumour
cells and healthy cells from the same patients, then compared them to find DNA
changes that were present only in the cancerous tissue.

This approach was made possible by new technology that has significantly
increased the speed of genome sequencing while reducing its cost. Each pair of
genomes took several months to read, at a cost of about £60,000. Similar
studies are now taking about six weeks and costing half as much, Professor
Stratton said, and capacity is improving all the time.

As the costs fall, it will become practical to sequence every cancer
patient’s tumour before he or she is treated, so that doctors can use the results
to choose the best therapeutic strategy.

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Emily SingerI write about the brain and other strange natural phenomena.